The Extent to Which Future Products Could Pose Different Types of Risks: Scenarios of Different Use Patterns of Future Biotechnology Products

In 1987, the National Academy of Sciences published a report that stated “[t]he risks associated with the introduction of [recombinant] DNA-engineered organisms are the same in kind as those associated with the introduction of unmodified organisms and organisms modified by other methods” and there is “no evidence that unique hazards exist either in the use of [recombinant] DNA techniques or in the movement of genes between unrelated organisms” (NAS, 1987). What is meant by “same in kind”? The present committee hypothesized that this phrase referred to the final risk-assessment endpoints identified in human health and ecological risk assessments. As these are the kind of assessments that have most commonly been conducted under the auspices of the Coordinated Framework, the committee interpreted its charge to identify “different types of risks” to mean that it should assess the degree to which risk-assessment endpoints identified in human health and ecological risk assessments for existing biotechnology products are likely to be similar to or different from the endpoints that would be selected when assessing risks for future biotechnology products. The question in the statement of task about different types of risks was also interpreted by the committee as a request to compare the risk hypotheses linking assumed routes of exposure to possible effects and the spatial and temporal scales used in existing risk assessments with those that may be needed for future products.

BOX 4-1

Risk-Analysis Refresher.

In the 2017 update to the Coordinated Framework (EOP, 2017), the regulatory agencies used a number of case studies to illustrate how the updated Coordinated Framework would be applied to products. To a large extent, the case studies review how a particular product would navigate the Coordinated Framework. For all the products reviewed, the route through the Coordinated Framework was relatively well defined. In its evaluation, the committee attempted to articulate scenarios for biotechnology products that could emerge over the next 5–10 years for which the path through the regulatory system would be less clear than for the case-study products. The committee also took into consideration whether risk-assessment endpoints for future biotechnology products would be different from existing biotechnology products.

To organize the scenarios, the committee considered different ways that future biotechnology products might be used or manufactured because exposure to a product or any potential effects on human health or an environment are connected to how a product is used or manufactured. The scenarios include products (including living organisms) that are designed to be released into an open environment and products that are manufactured in contained systems (albeit with limited environmental releases). The committee also examined products with intended or unintended reversible effects as well as products with intended or unintended irreversible effects. It considered exposure of biotechnology products to people or the environment but did not consider human or environmental exposure to compounds produced from biotechnology products.¹ The committee did not attempt to review all available risk assessments and risk-management decisions for existing biotechnology products available in the public domain or prepare problem formulations for possible future biotechnology products. Rather, the committee evaluated several scenarios in which future biotechnology products may be used or manufactured to illustrate key issues and concepts that are required to address the statement of task’s question about different types of risk. Some of the scenarios are drawn from two National Academies of Sciences, Engineering, and Medicine reports (NASEM, 2016a,b), while others are drawn from Drinkwater et al. (2014) and presentations made to this committee. The scenarios provided below are intended to be illustrative of the issues that need to be considered to determine similarity in risks of existing biotechnology products with those risks that may be associated with future biotechnology products.

Risks or Lack of Risks That Are Well Understood

As noted in the introduction of the chapter, the committee interpreted the first question in this part of the statement of task as a request to reflect on the degree to which regulatory human health and ecological risk-assessment endpoints used in risk assessments for existing biotechnology products are likely to be similar to or different from the endpoints that would be selected when assessing risks for future biotechnology products. The second question concerns risks or lack of risks of biotechnology products that are well understood. The term “well understood” was interpreted to mean situations when uncertainty in estimates of risk does not preclude a description of the possible risks consistent with the goals and objectives established during the problem-formulation phase of a risk assessment (see EPA, 1998; NRC, 2009; Box 4-1). However, even with that interpretation, the committee’s statement of task was difficult to address given the ambiguity of the phrase “risks or lack of risk.” Terms such as “lack of risks,” “low risks,” “minimal risks,” or “acceptable risks” contribute to linguistic ambiguity (NASEM, 2016a) and do not provide a meaningful framework from which to distinguish between scenarios of a product’s use in which there are “risks” versus situations where there is a “lack of risks.”

Because risk assessments available for existing biotechnology products do not, in general, employ probabilistic estimates of risk, but rather use deterministic expressions of risks (Box 4-2), the committee could not quantitatively address the extent to which risks or the lack of risks are well understood. Existing risk assessments typically characterize risks in a qualitative or deterministic manner, which precludes the means to quantitatively compare risks of existing and future biotechnology products and of biotechnology products to nonbiotechnology products designed for similar use patterns. Advancing quantitative risk assessments will be useful generally, given the characteristics of future open-release products (for example, the mechanisms of action, degree of reversibility and recovery, or movement within ecosystems). There is a need to advance risk-assessment techniques for potential adverse outcomes that have not been rigorously addressed for both biotechnology products and environmental stressors⁴ in general (NRC, 2013; NASEM, 2016a). Given the nature of the use patterns for future open-release products, spatially and temporally explicit risk assessments will also facilitate a more insightful identification of risk patterns.

Risks That Are Not Well Understood

Although risk-assessment endpoints for human health and environmental effects for existing and future biotechnology products will likely be similar (assuming, for example, similar manufacturing controls, use patterns, and properties of the products), the magnitude of the risks may change, the pathways could be more complex and multidimensional, and existing risk assessments have limitations. It is not always clear in existing risk assessments how assessment endpoints were selected or how the dimensionalities of the risk assessments were considered. Furthermore, existing risk assessments are generally comparative risk assessments—that is, they rely in large part on the comparison of a new biotechnology product to an existing nonbiotechnology product. Future products of biotechnology will involve more complex comparisons that, for example, potentially encompass multigene traits in consortia deployed in novel environments and management scenarios, and the new products may not have a counterpart or precedent to allow a ready means for an “as safe as” comparison to a product that already exists. The comparative risk-assessment process may, however, be more easily applied to human health risk assessments than to ecological risk assessments. Finally, it is difficult and not typical to incorporate social and cultural factors into existing risk assessments, yet these factors may ultimately affect human health and ecological risk (for example, social systems and variability in use of products). In addition, social and cultural values, including social and cultural risks, are not usually included in regulatory risk assessments and are difficult to assess.

BOX 4-2

Deterministic Versus Probabilistic Risk Assessment.

Products Without Comparators. Existing biotechnology risk assessments are guided by comparative risk approaches and are informed by comparisons to nonbiotechnology counterparts that help establish the “as safe as” criteria used by regulatory decision makers. As described in Chapter 2, existing biotechnology products have typically involved a host (the organism into which new material is introduced) and a source (the organism from which the new material was taken). For example, for a GE insect-resistant variety of corn, the corn is the host organism and the bacterium Bacillus thuringiensis (Bt) is the source organism. In the comparative risk-assessment paradigm, the GE corn variety is compared against a genetically similar variety of corn that does not contain the GE trait. The two varieties are compared in terms of nutrient and chemical composition to ascertain if there are unintended differences (the GE trait is an intended difference). This comparison includes toxicity testing and allergenicity screening to help identify any potential human health issues related to intended or unintended effects from the GE trait.

With the advancement of biotechnology from recombinant-DNA technology to genome engineering, the use of comparators is becoming more challenging, even for GE crops (EFSA, 2011). Furthermore, transformations can be made in host organisms that are less well characterized than corn. For example, genome-editing technologies allow product developers to make changes in genomes of nearly any host organism for which there is a genome sequence available, from microbes to insects to mammals (Reardon, 2016). There may not be baseline data on the nontransformed counterpart host. Furthermore, novel gene sequences—including synthetic ones—can be introduced into host organisms; there may be no nonbiotechnology product to which they can be compared.

If potential off-target effects of new technologies, such as genome editing, are similar to those that occur naturally—for example, point mutations or epigenetic changes—and the probability of off-target effects is not substantially different from the background rate of such changes, then any additional risk (that is, beyond that associated with the intended target of genome-editing technology) is low. On the other hand, the range of genome-editing techniques is rapidly expanding, and if certain new technologies cause off-target effects that do not typically occur naturally or increase the number of such changes, then this may pose an additional challenge for comparative risk assessment. Note that conventional-breeding techniques such as mutation breeding in plants could increase the extent and the range of types of off-target effects to a much greater extent than existing genome-editing techniques (NASEM, 2016b). With rapid changes in and lowering costs of genome sequencing and genome-interrogating technologies (see Chapter 2), genome-wide identification of off-target effects is increasingly straightforward. However, what remains a challenge is evaluating whether any off-target effects pose a risk because of the difficulty in obtaining proper comparators. Finally, for organisms made by inserting entirely new pathways of genes derived from multiple unrelated sources or consortia of organisms engineered with multiple genes, how a product developer or regulator would conduct protein toxicity testing is complicated. Synergistic effects of multiple genes and organisms compound such testing, and it might not be accurate to test each organism or gene separately. In these cases, basic biology and ecology studies may be necessary to develop baseline environmental behaviors, as in new knowledge about gene transmissibility, persistence in the environment, and toxin production before small-scale environmental release.

On a related note, products without comparators do not have a clear path already charted through the U.S. regulatory system. The degree to which risks associated with a new type of product are “well understood” is a subjective determination, but formal uncertainty analyses can help determine when a reduced level of regulatory scrutiny may be warranted. Use of a biological component or system that has a history of safe use provides an existing regulatory path with known nonbiotechnology comparators and clear risk-assessment endpoints, whereas using an unfamiliar component or system does not. Future biotechnology products may be unique and therefore lack adequate precedents. For example, the GE mosquito developed by the company Oxitec was a first-of-its-kind product; it was genetically engineered to carry a gene that would render its offspring sterile with the goal of effectively eradicating the mosquito population (Aedes aegypti) that, among other things, carries dengue, chikungunya, and Zika viruses. The developer and the regulatory agencies both shared uncertainty on the front end as to whether the GE mosquito should be regulated by EPA under FIFRA as an insecticide (because it kills mosquitoes) or by the U.S. Food and Drug Administration (FDA) as a new animal drug (the pathway that was used for genetically engineered salmon). After a number of years of agency deliberations, in August 2016 FDA ultimately released a final environmental assessment and a finding of no significant impact, agreeing with Oxitec’s environmental assessment that its proposed field trial would not have significant impacts on the environment. However, FDA’s assessment was not a quantitative, probabilistic one and was not based on field data looking for harm to nontarget species or to ecosystems; field data from other countries only looked at the efficacy of population suppression (FDA, 2016). The committee heard a similar concern about a lack of clarity with regards to the regulatory path for engineered microbes. The microbes were designed for open-environmental release to extract gold and copper from low-grade ore. An invited speaker emphasized that there was ambiguity about which regulatory agency would be responsible for the product, what data would be required by the agency, and what nontransformed host would serve as the comparator in a risk assessment (DaCunha, 2016).

Social and Cultural Effects. Methods to incorporate social and cultural values into risk analysis are limited because they often cannot be put on the same scale as health risks, environmental externalities, and monetized costs and benefits. However, some risk-analysis frameworks have been developed to incorporate values of various publics during the problem-formulation or risk-management stage, when other options are compared to the proposed action of releasing a technological product (Nelson et al., 2004). Previous National Academies reports have also emphasized the importance of public participation in the risk-analysis process, particularly in risk characterization (which involves complex, value-laden judgments) and problem formulation, where public involvement can improve acceptance of the analysis (Box 4-3) and improve the analysis for the purposes of risk management (NRC, 1996, 2008, 2009; NASEM, 2016a).

BOX 4-3

Public Confidence.

Future products of biotechnology will be more complex in terms of their interactions with their environment and society, and more research may be needed to develop methods for governance systems that integrate ethical, cultural, and social implications into formulation of risk-assessment endpoints and risk characterization in ways that are meaningful. At the same time, it may not be feasible or even justified for all new biotechnology products—for instance, products with which there is already familiarity or products that will not be released into the environment. Genetically engineered organisms used in the research laboratory to develop new chemical synthesis methods are not likely to require the same level of public dialogue according to decision criteria for public engagement proposed by several scholars and think-tanks as will products that have more uncertainty associated with them, such as organisms with gene drives (Funtowicz and Ravetz, 1995; NRC, 1996; Renn, 2005; NASEM, 2016a).

Existing Scientific Capabilities in the Federal Workforce

The committee made use of the FedScope database within the U.S. Office of Personnel Management to ascertain the types of expertise within the regulatory agencies. The database provided information about the trends in number of staff with each type of expertise for the fiscal years 2011–2015.⁷ From the list of professional occupations provided in the database, the committee selected 33 that it surmised would be necessary to the regulatory responsibilities of EPA, FDA, or USDA–Animal and Plant Health Inspection Service (APHIS) personnel; the search returned results for at least one agency in 25 of the occupations.⁸ Figures 4-1 through 4-6 show the employment trends for the occupations in each agency. There are two figures per agency to address issues of scale. Professions or years which returned a value of “NA” in the database are not included in the figures.

The committee recognizes that the data provided in Figures 4-1 through 4-6 are not as specific as would be desired. The committee was primarily interested in the expertise available with FDA’s Center for Food Safety and Applied Nutrition and Center for Veterinary Medicine, EPA’s Office of Chemical Safety and Pollution Prevention, and USDA–APHIS’s Biotechnology Regulatory Services. This level of resolution was not available; as a result, the number of full-time employees (FTEs) in the regulatory agencies whose activities are most directly relevant to nonmedical biotechnology products is likely well below those depicted in the figures. Nevertheless, the information returned through the committee’s search of the FedScope database shows that, for much of the expertise relevant to regulation of biotechnology, the number of employees has fallen over the period of time covered in the database. For some applied disciplines important to understanding the use and deployment of biotechnology products, the decrease in numbers is a cause for concern (for example, the numbers of plant pathologists, soil scientists, fisheries biologists, and agricultural engineers within EPA) given the committee’s prediction that the number and novelty of future biotechnology products will increase. Because the FTE data available to the committee likely overestimate the breadth and depth of regulatory agency staff, the trends in the federal workforce raise the possibility there may not be sufficient capacity to meet future regulatory demands. There is the possibility of using contract scientists to manage the day-to-day workload of review, analysis, and summarization of regulatory submissions. Agencies within the Coordinated Framework have and do maintain contract personnel and have this built into agency budgets. Proper utilization of such outside expertise will require appropriate training and oversight to ensure the quality of regulatory reviews is maintained.

FIGURE 4-1

Professions of interest at the U.S. Environmental Protection Agency with fewer than 300 employees, fiscal years 2011–2015. DATA SOURCE: U.S. Office of Personnel Management. FedScope database, employment trend cubes. Available at https://www.fedscope.opm.gov/etrend.asp. (more...)

FIGURE 4-2

Professions of interest at the U.S. Environmental Protection Agency with more than 400 employees, fiscal years 2011–2015. NOTE: General Natural Resources Management and Biological Sciences includes employees hired with expertise in biological (more...)

FIGURE 4-3

Professions of interest at the U.S. Food and Drug Administration with fewer than 150 employees, fiscal years 2011–2015. DATA SOURCE: U.S. Office of Personnel Management. FedScope database, employment trend cubes. Available at https://www.fedscope.opm.gov/etrend.asp. (more...)

FIGURE 4-4

Professions of interest at the U.S. Food and Drug Administration with more than 200 employees, fiscal years 2011–2015. NOTE: General Natural Resources Management and Biological Sciences includes employees hired with expertise in biological sciences, (more...)

FIGURE 4-5

Professions of interest at the U.S. Department of Agriculture’s Animal and Plant Health Inspection Service with fewer than 150 employees, fiscal years 2011–2015. NOTE: This figure has been updated since the prepublication release. The (more...)

FIGURE 4-6

Professions of interest at the U.S. Department of Agriculture’s Animal and Plant Health Inspection Service with more than 300 employees, fiscal years 2011–2015. NOTE: General Natural Resources Management and Biological Sciences includes (more...)

Enhancing Federal Expertise Through External Scientific Advisory Committees

The agencies can and have supplemented their internal expertise by making use of external advisory committees. Independent federal advisory committees can not only assist with scientific peer review on issues of human health and ecological risk assessment but can also provide input on issues such as risk-assessment methodology, environmental modeling, life-cycle analyses, sustainability, and environmental justice, among others, which may become more relevant in assessing risks and benefits of future products if the conception of risk is broadened (see Box 3-1). EPA has used such committees to provide independent, external peer review, with public comment, on specific, well-defined risk-assessment methodology and assessment issues for specific biotechnology products.⁹ In the context of pesticidal biotechnology products, EPA has used its science advisory panels (SAPs) to review risk assessments and resistance management plans for Bt plant-incorporated protectants since the mid-2000s.¹⁰ In 2014, the FIFRA SAP reviewed EPA’s proposed problem-formulation approach for RNA interference (RNAi) technology in anticipation of future human health and ecological risk assessments of specific RNAi products (EPA, 2014a). Consistent with an iterative process in advancing risk-assessment approaches for a new technology, EPA convened a SAP in September 2016 to review a draft assessment for a specific RNAi plant-incorporated protectant (EPA, 2016c).

Other agencies acting within the Coordinated Framework have utilized programmatic environmental impact statements to elicit public input as a means to consider need for future regulation for biotechnology products. For instance, USDA–APHIS undertook programmatic environmental impact statement activities in 2004 for the purpose of rulemaking to determine if their regulatory remit for biotechnology regulation could be clarified and expanded (USDA–APHIS, 2004), and it was involved in a similar process at the time the committee was writing its report (USDA–APHIS, 2016). In addition, USDA–APHIS has sponsored third-party activities to gain expert input that was subsequently reflected in views and approaches used in biotechnology risk assessment (Traynor and Westwood, 1999). USDA–APHIS has also directly sponsored expert workshops (Rose et al., 2006). There also have been expert meetings hosted by the former interagency Agricultural Biotechnology Risk Analysis Task Group to understand research priorities (NSTC, 2007). Agencies responsible for regulating future biotechnology products can also build from experience to proactively gain advice and input on proposed risk-assessment approaches for other future products and assessment techniques in areas like nanotechnology (EPA, 2009), computational toxicology (EPA, 2011), spatially explicit ecological assessments (EPA, 2015), and pollinator protection (EPA, 2012).

EPA, FDA, and USDA–APHIS have used independent external scientific input and review several times in the past. For example, EPA sought input from the National Research Council (NRC, 2012) to provide advice on future environmental science and engineering challenges and technological advances and to assess the overall capabilities of the agency to meet emerging and future mission challenges. One of the recommendations was to “[e]ngage in a deliberate and systematic ‘scanning’ capability involving staff from [EPA’s] ORD [Office of Research and Development], other program offices, and the [EPA regional offices]. Such a dedicated and sustained ‘futures network’ (as EPA has called groups in the past with a similar function), with time and modest resources, would be able to interact with other federal agencies, academe, and industry to identify emerging issues and bring the newest scientific approaches into EPA” (NRC, 2012:11). Consistent with this horizon-scanning recommendation, in 2016 EPA shared a preliminary view of emerging and potential issues, which included the inevitability of transformational biotechnology products (Greenblott et al., 2016).

The benefit of this input from external experts is reflected in guidance that lays the groundwork for implementation of strengthened approaches for risk assessment. For instance, guidance for identifying and selecting ecological risk-assessment endpoints (including those that address ecological goods and services) across biological, spatial, and temporal scales have been developed (for example, EPA, 2003, 2016g), and EPA has summarized experiences gained in several case studies that assessed the human health and ecological risks of exposure to combinations of disparate chemical, biological, and physical stressors. These case studies also highlight the importance of engaging stakeholders throughout the risk-assessment phases and risk management (Gallagher et al., 2015; see also Box 4-3). The U.S. Fish and Wildlife Service (FWS), the National Marine Fisheries Service (NMFS), USDA, and EPA were in the process of implementing recommendations from the 2013 National Research Council report Assessing Risks to Endangered and Threatened Species from Pesticides at the time the committee was writing its report.¹¹ EPA’s Risk Assessment Forum has developed peer-reviewed white papers on the use of probabilistic human health and ecological risk assessments (EPA, 2014b) in response to the 2013 Institute of Medicine report on uncertainty in environmental decision making (IOM, 2013). Probabilistic human health risk assessments are performed on a routine basis for food-use pesticides (EPA, 2016a) based on advice from the FIFRA SAP. Probabilistic methods have been developed for some ecological risk-assessment scenarios (NRC, 2013; EPA, 2016e) and have been employed in a limited number of cases. Ongoing research to advance computational toxicology techniques, including high-throughput screening, illustrates EPA’s commitment to advance 21st-century approaches to assess chemical stressors (NRC, 2007) and develop and employ the information-technology infrastructure needed to manage and analyze large data sets (for example, see EPA, 2016f).

EPA, USDA, and USGS already maintain and employ large geospatial data sets to support human health and ecological risk assessments¹² and agriculture and natural resource research and management within the governance of the Federal Geographical Data Committee (NRC, 2013). Research is ongoing to develop the data, models, and tools to expand community stakeholders’ capabilities to consider the social, economic, and environmental impacts of decision alternatives on community well-being; develop the causal relationships between human well-being and environmental conditions; develop and implement monitoring designs and indicators to support national, regional, and state reports of environmental condition; and advance tools and metrics to support life-cycle analyses (Yeardley et al., 2011; EPA, 2016d). The agencies also have established processes to address cross-cutting research and scientific issues, including dialogue with stakeholders,¹³ which could be expanded to complement cross-cutting issues relevant to the Coordinated Framework and future research and risk-assessment needs.

Another example of an external advisory group is the EPA Pesticide Program Dialogue Committee (PPDC),¹⁴ which was established in 1995 as a forum for a diverse group of stakeholders—environmental and public-interest groups, pesticide manufacturers, trade associations, commodity groups, public health and academic institutions, federal (including USDA, FDA, FWS, NMFS, and the Centers for Disease Control and Prevention) and state agencies, and the general public—to provide feedback to EPA on various pesticide regulatory, policy, and program implementation issues. The PPDC has provided advice to EPA in implementing far-reaching changes in risk-assessment and risk-management approaches mandated with passage of the Food Quality Protection Act in 1996 and provided input on issues including implementation of 21st-century toxicology testing and nonanimal testing alternatives, endangered species and pollinator protection options, classification systems for reduced-risk pesticides, and approaches for documenting label claims, among others. The PPDC also provided feedback on EPA’s development and implementation of public review and comment processes for proposed new pesticide registration decisions (EPA, 2016b) and the reevaluation of registered pesticides (including problem formulation, draft risk assessments, and proposed regulatory decision steps¹⁵). This EPA advisory committee could be employed to help guide the development of a governance approach for pesticidal biotechnology products in conjunction with the Coordinated Framework.

Independent external advice and input can help expand the ability of a federal agency to meet its future scientific challenges. Successful implementation of recommendations from an advisory committee is contingent on the breadth and depth of an agency’s workforce. Downward trends in the staffing of certain areas of expertise at regulatory agencies (summarized in Figures 4-1 through 4-6) raise concerns that the staff may not have sufficient time or skills to take advantage of external advice and prepare for the future.

Federal Research Funding to Advance Risk Analysis on Future Biotechnology Products

In an attempt to better ascertain the nature and extent of federal research designed to support risk analyses of biotechnology products, the committee solicited input from relevant agencies through a request for information (RFI) keyed to programmatic work addressing risk analysis for products of biotechnology. The questions posed in the RFI (see Appendix C) were derived, in part, from the report Creating a Research Agenda for Ecological Implications of Synthetic Biology, published in 2014 following two workshops organized by the Massachusetts Institute of Technology Program on Emerging Technologies and the Woodrow Wilson Center’s Synthetic Biology Project (Drinkwater et al., 2014) and from a workshop and Delphi study on synthetic-biology governance funded by the Sloan Foundation and hosted by North Carolina State University’s Genetic Engineering and Society Center (Roberts et al., 2015). The committee was interested in programmatic work related to fundamental and applied research efforts that can inform human, animal, and ecological risk assessments and socioeconomic costs and benefits. Research related to potential risks of future human drugs or medical devices was not included in the committee’s statement of task and therefore was not part of this RFI, except to the extent such research may be broadly applicable to other biotechnology products.

The committee sent the RFI to 28 federal offices and received responses from 17. Twelve of the 17 had information to share that was relevant to the committee’s request. The RFI recipients are listed in Appendix C. The RFI specifically asked about the ongoing research the agencies had with regards to

• The nature and extent to which future biotechnology products were similar to or different from nontransformed (nonbiotechnology) products serving as comparators.
• Off-target gene effects¹⁶ and phenotype characterization of future biotechnology products.
• Impacts of future biotechnology products on nontarget organisms.
• Gene fitness, gene stability, and propensity for horizontal gene transfer in future biotechnology products.
• Measures designed to control organismal traits and mitigate risk in the event of intentional or accidental release of future biotechnology products.
• Life-cycle analysis of future biotechnology products.
• Monitoring and surveillance of future biotechnology products.
• Modeling to inform risk-based hypotheses, collect data to reduce uncertainties, and provide findings or predictions in risk characterization with regards to future biotechnology products.
• Economic costs and benefits of future biotechnology products.
• Social costs and benefits of future biotechnology products.

The committee also included an “other” category to catch any other areas of research not described above in the event any of the agencies receiving the RFI had additional information to share. Information falling into this category is not included in the following figures but is described within the text.

EPA reported it had no ongoing research directly tied to any one area of the RFI. However, the agency did provide the committee with information regarding efforts within its Office of Research and Development that would enhance risk-assessment capabilities and could be applied to biotechnology. It is worth noting that EPA previously funded intramural and extramural biotechnology research programs, but these activities were discontinued in 2012. At the time the committee was writing its report, EPA possessed some capacity and capability for implementing probabilistic ecological risk assessments (as noted above) but had done so only on a limited basis for nonbiotechnology pesticides; models appropriate for ecological risk assessments of biotechnology products had not been developed.

USDA reported a total of approximately $13.23 million invested during 2012–2015 across 10 research areas (Figure 4-7). The response from USDA reflects investments through its Biotechnology Risk Assessment Grants (BRAG) program, which is jointly administered by USDA’s Agricultural Research Service (ARS) and National Institute of Food and Agriculture. The BRAG program receives input regarding its program priorities through multiple regulatory agencies that have an interest in the environmental risk related to the introduction of GE organisms, including USDA–APHIS, EPA, and FDA. About 75 percent of BRAG award recipients for the years included were scientists with land-grant universities or USDA–ARS.

The committee also contacted and received feedback in response to the RFI from several federal agencies that are not primary agencies within the Coordinated Framework. Of the seven offices at the National Science Foundation (NSF) that were sent the RFI, the committee received responses from three of them: the Division of Industrial Innovation and Partnerships, the Division of Social and Economic Sciences, and the Division of Chemical, Bioengineering, Environmental and Transport Systems. These divisions reported total investments of approximately $95.8 million during 2012–2016 (Figure 4-8); additionally, they reported approximately $44.8 million in investments fitting under “other,” which primarily involved the product-development research and not research pertaining to the risk assessment of those products. The U.S. Army Corps of Engineers invested $2.08 million during the same time period ($1.24 million in fitness, gene stability, and horizontal gene transfer; and $0.84 million in monitoring and surveillance).

FIGURE 4-7

Spending by the U.S. Department of Agriculture on programmatic work related to fundamental and applied research efforts that can inform human, animal, and ecological risk assessments and socioeconomic costs and benefits, 2012–2015. NOTES: Life-cycle (more...)

FIGURE 4-8

Spending by the National Science Foundation on programmatic work related to fundamental and applied research efforts that can inform human, animal, and ecological risk assessments and socioeconomic costs and benefits, 2012–2016. NOTES: SES and (more...)

The Office of Naval Research (ONR), the Defense Threat Reduction Agency (DTRA), and the U.S. Army Research Laboratory (ARL) provided the committee with information pertaining to their investments in 2012–2016; most of this research was on biotechnology products (falling under the “other” category) and not directly related to risk-analysis research areas outlined in the RFI. ONR reported approximately $32.9 million, DTRA reported approximately $149.8 million, and ARL reported approximately $88 million in awards pertaining to research and development of biotechnology products.

The Intelligence Advanced Research Projects Agency (IARPA) and the Defense Advanced Research Projects Agency (DARPA) indicated that they were initiating efforts in the areas outline by the RFI as well as research into future products of biotechnology. IARPA indicated to the committee (Julias, 2016) that a 2016 research initiative addressing several of the topics in the RFI was under way and will address comparators; computational modeling; off-target gene effects and phenotypic characterization; fitness, genetic stability, and horizontal gene transfer; control of organismal traits; and impact on nontarget organisms. Although the total level of future investments was not provided, IARPA anticipated the majority of funding would initially address comparators and computational modeling. At the time the committee was writing its report, DARPA was launching a “Safe Genes Program” to support responsible innovation while mitigating the risk of unintended consequences of genome editing and derivative technologies, including gene drives.¹⁷ The level of future research investments for this program was not publicly available.

The Office of Biological and Environmental Research within the U.S. Department of Energy (DOE) indicated investments of approximately $15 million per year between 2012 and 2016 made by the Genomic Science program. The committee was unable to get resolution as to the specific areas (as outlined by the RFI), but it appeared that awards had gone toward the control of organismal traits or future products of biotechnology (the latter falling under the “other” category). Other agencies that responded to the RFI (U.S. Air Force Office of Scientific Research and FDA) indicated that their intramural and extramural programs do not currently address the topics identified by the committee. The committee also heard from the National Invasive Species Council (NISC) Secretariat, which provides support to the NISC to coordinate control of invasive species across the federal government. The council has interest in and has supported work in this area in the past but was not directly funding the areas outlined in the RFI at the time the committee was writing its report.

In summary, for those federal agencies that responded to the RFI, risk-analysis research resources cumulatively totaled to $111.08 million over the 2012–2016 period (Table 4-1). Of note is the lack of any research funding by FDA to address risk analyses for future biotechnology products. Although EPA did not have direct investments for risk analyses of future biotechnology products, its efforts in risk-analysis research in other areas can be applied toward biotechnology products.

A 2015 Woodrow Wilson Center report estimated that in 2008–2014 the U.S. government invested $820 million in synthetic-biology research (with a significant increase in 2010–2014) with DARPA, the U.S. Department of Defense (excluding DARPA), DOE, NSF, and the National Institutes of Health investing the majority resources (Wilson Center, 2015). Of the total investment, the Wilson Center estimated less than 1 percent was invested in risk research and approximately 1 percent was invested in ethical, legal, and social issues. The results of the committee’s RFI indicated approximately $6.98 million was invested in social research in 2012–2015, which is fairly consistent with the Wilson Center findings. However, assuming a flat budget for total synthetic-biology research in 2015 as compared to 2014 (that is, approximately $220 million in 2015 or an estimated total of $1.04 billion in 2008–2015), the results of the RFI indicate approximately 9 percent of the total ($89.92 million when excluding social research) was invested in risk–benefit research. Excluding research on economic costs and benefits during the period 2012–2015 ($20.93 million), risk research during that period (approximately $68.98 million) would represent approximately 7 percent of the total synthetic-biology research portfolio.

The results of the Wilson Center study and the committee’s RFI indicate that from the “outside looking in” it is difficult to ascertain the level of research funding to support risk analyses, and it appears it may also be a challenge for the U.S. government to aggregate investment totals across agencies. Consequently, the committee acknowledges uncertainty in its estimates of risk-analysis research investments, due the level of resolution different agencies provide for their yearly budgets. The committee also realizes there may be related research efforts outside of synthetic biology that can support future risk-analysis methods (for example, research undertaken by USDA’s Agricultural Research Service and the Agricultural Experiment Stations at public universities). However, the estimates suggest that research in specific areas such as modeling and life-cycle analyses, which are critical for supporting premarket risk assessments and socioeconomic cost–benefit analyses, represent 0.02 percent and 0.17 percent, respectively, of the total synthetic-biology research investment. Monitoring and surveillance research, which is critical to supporting post-market assessments and implementing risk-mitigation measures, represents approximately 1.4 percent of the total research portfolio. Research concerning comparators; off-target gene effects and phenotypic characterization; impacts on nontarget species; gene fitness, stability, and horizontal gene transfer; and control of organisms (containment and confinement) combined to represent approximately 5 percent of the total synthetic-biology research investment. These research areas can support both premarket and post-market risk analyses. It is difficult to determine the appropriate level of investment for risk research to support oversight of future biotechnology products; however, the sense of the committee is that the current level is insufficient.

TABLE 4-1

Federal Investment in Risk-Analysis Research, 2012–2015.

The committee is also concerned that the current U.S. government risk-analysis research portfolio may not be planned in a manner that can maximize its return on investment. It is encouraging that USDA’s BRAG program includes other federal agencies, including EPA and FDA, in identifying research priorities; however, there is no indication that these interactions include regulatory risk assessors, risk managers, and researchers working together to vet and adapt research products for use in risk assessments and socioeconomic cost–benefit analyses. Based on the responses to the RFI, there does not appear to be significant interaction between DARPA and other agencies in the U.S. Department of Defense, DOE, and NSF with USDA, EPA, and FDA regulators in research planning or in envisioning a new paradigm for advancing risk-analysis approaches for future biotechnology products.

While the reported research portfolio may be relevant to the risk-analysis needs for future biotechnology products, it is not clear that it is responsive to the nature and extent of future challenges facing public- and private-sector risk assessors, risk managers, and other interested and affected parties. Finally, the committee notes that the financial resources needed to establish an adequate research portfolio for the United States need not fall solely on the U.S. government and the nation’s tax payers. The U.S. government may want to explore establishing open and transparent approaches to integrate and optimize public investments, private investments, and public–private partnerships to realize the needed resources to support development of a responsive, nimble, and robust risk-analysis paradigm.

The consequences of current levels of intramural and extramural funding in research and to support future risk-assessment needs suggest the number of products poised to enter the marketplace in the coming 5–10 years may outpace the means and capacity for voluntary- or regulatory-based risk–benefit assessments to inform premarket decision making or post-market oversight, including environmental monitoring.